Malaria is a mosquito-borne disease which kills one to three million people per year and debilitates another 100 million people at any given time. This disease is resurging in many areas of the world that had almost been freed of it 40 years ago. The most intractable problem contributing to malaria resurgence and our ineffectiveness in attempts to suppress it has been the development of physiological and behavioral resistance in the mosquito vectors to insecticides, and resistance in the pathogens to the drugs used to reduce mortality and morbidity in infected humans. An effective anti-malaria vaccine continues to elude researchers, and there is concern that it will not be possible to administer a vaccine adequately to the people most in need even if one is developed. The best hope for ultimate worldwide suppression of malaria lies in novel control strategies incorporating genetically altered mosquito vectors. It is not yet possible to genetically transform mosquitoes, but the solution to this problem is inevitable and seems imminent. Meanwhile, great efforts are being made to analyze a variety of genes for their potential utility in the genetic alteration of mosquitoes. One particularly promising system is that of the vitellogenin receptor (VgR) and its ligand, vitellogenin (VG). IN a critical process in the life-history of the mosquito ( and all other egg-laying animals), membrane-bound VgRs on the surface of the oocyte specifically recognize, bind and internalize VG ( the major yolk protein precursor) which is circulating the hemolymph after a blood meal. The Vg is stored as the major component of yolk, and provides nourishment for the embryo. The long-term objective of this grant proposal is to characterize the VgR from the African malaria mosquito (Anopheles gambiae), the most efficient disease vector in the world and to elucidate the molecular basis of the receptor's specific interaction with Vg. The information obtained from this study should prove useful in designing novel mosquito control strategies. For example, introduction of a factor into a mosquito population that disrupts this critical process of VgR/Bg binding will have a negative impact on the population. In addition, it may be possible t o exploit the VgR/Vg interaction as a mechanism for foreign gene delivery in future mosquito transformation systems.